Type II or non-insulin dependent diabetes mellitus (NIDDM) is estimated to affect 5% of the world's population. Considering the additional 10-11% of the adult population with impaired glucose tolerance (which imposes a greater than 6-fold increased risk of developing NIDDM), 8-10% of adults either have, or will develop, NIDDM. Approximately 20% of the members of the US population over 65 years of age are diabetic. The medical consequences of this disorder are staggering. The complication rates in NIDDM patients are equivalent (per year of disease) to the much smaller number of individuals with type I, insulin-dependent diabetes. Diabetes is the leading cause of blindness, end stage renal disease and amputations in the US, and contributes significantly to the high prevalence of dyslipidemias and hypertension. The enormous physical and psychological burdens imposed by this disease are only partly reflected in the estimated $25 billion dollars spent annually on its treatment in the US alone. There is a strong genetic predisposition to NIDDM, the expression of which is facilitated by the presence of obesity. Over 60% of individuals with NIDDM are obese. The mechanisms by which obesity predisposes to NIDDM is not known, but it is likely that obesity stresses the pancreatic beta cells by diminishing the action of insulin on glucose metabolism. The goal of this proposal is to identify the genes which, in the presence of obesity, predispose to the development of NIDDM. The complexity of the genetics of NIDDM in humans favors the initial use of simpler animals models to identify candidate genes for NIDDM- susceptibility and resistance. Using well characterized mouse and rat genetic models of obesity-diabetes, such genes will be identified. These genes will be then be examined by genetic linkage techniques in human families in which NIDDM is present. Ultimately, knowledge of the structure/action of such genes can be used to prevent or treat NIDDM.